GSBS Dissertations and Theses

Approval Date

3-19-2015

Document Type

Doctoral Dissertation

Academic Program

Interdisciplinary Graduate Program

Department

Biochemistry and Molecular Pharmacology

First Thesis Advisor

Oliver Rando, MD, PhD

Keywords

Genomic Imprinting, Metabolism, Inheritance Patterns, Paternal Exposure, DNA Methylation, DNA, Ribosomal DNA, Diet, Genetic Epigenesis, Epigenomics, Fertilization, Phenotype, Spermatozoa

Subjects

Dissertations, UMMS; Genomic Imprinting; Metabolism; Inheritance Patterns; Paternal Exposure; DNA Methylation; DNA, Ribosomal DNA, Ribosomal; Diet; Epigenesis, Genetic; Epigenomics; Fertilization; Phenotype; Spermatozoa

Abstract

The following work demonstrates that paternal diet controls medically important metabolic phenotypes in offspring. We observe transmission of dietary information to the zygote via sperm, and this information evades reprogramming that typically occurs after fertilization. Cytosine methylation is implicated as a major contributor to meiotic epigenetic inheritance in several transgenerational phenomena. Our extensive characterization of the sperm methylome reveals that diet does not significantly affect methylation patterns. However, we find that extensive epivariability in the sperm epigenome makes important contributions to offspring variation. Importantly, coordinate cytosine methylation and copy number changes over the ribosomal DNA locus contributes to variation in offspring metabolism. Thus, rDNA variability acts independently of postadolescent paternal diet to influence offspring metabolism. Therefore, at least two mechanisms exist for epigenetically controlling offspring metabolism: stochastic epivariation and diet acting by an unknown mechanism to further modulate metabolism. This work argues that an offspring's phenotype can no longer be viewed solely as the result of genetic interactions with the developmental environment - the additional influences of paternal environment and inherited epigenetic variability must also be considered. These findings reveal novel contributions to metabolism that could revolutionize how we think about the risk factors for human health and disease.

DOI

10.13028/M27S3C

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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